The achievements of the 20th century biology - decoding of the structure of proteins, DNA molecule and then of the human genome - have promoted the rapid progress of the associated sciences. But penetrating into the secrets of the mechanism of heredity offers not only new opportunities of healing of different disorders but is also fraught with hidden threats. These problems were on the agenda of the First International Conference "Molecular Medicine and Biosafety" which met in Moscow in October 2004.

DIAGNOSIS FROM ONE SINGLE CELL

A representative international forum of this kind-with the participation of the leading experts in this new and rapidly progressing branch of medical science-was held in this country for the first time. It was organized by the Ministry of Health and Social Development of the Russian Federation, the Russian Academy of Sciences, the Russian Medical Academy, the Moscow Medical Academy (MMA) named after I. Sechenov, the international Scientific and Technical Center, the TEMP Center of New Medical Technologies. The organizers tried to focus the efforts of the international scientific community on dealing with priority problems and to draw the attention of the powers that be to the risk of Russia lagging behind in the field of biotechnologies (its estimated share on the present world market is less than one percent).

Functioning now in the United States are 613 centers of molecular medicine and there are more than 200 such centers in Western Europe. In Russia the most significant research in this field is conducted by the All-Russia Research Center of Molecular Diagnostics and Treatment; Scientific Research Institute of Molecular Medicine (MMA) named after I. Sechenov; the Center of Molecular Medicine of Lomonosov Moscow State University; the St. Petersburg State Medical University named after I. Pavlov and several other centers of the Russian Academy of Sciences and the Russian Medical Academy.

So, what can one say about this new branch of medical science and, over the past few years, of clinical practice? Its main postulate is that for every illness and pathological manifestation there is a molecular "target" which can be used both - for diagnostics and for the application of medical drugs. This postulate was formulated in his presentation at the conference by Acad. M. Paltsev, member of RAS and RAMS, Rector of the Sechenov Medical Academy. Medical scientists can locate this "evasive target" and every infectious pathogene by using rapidly progressing instrumental methods (laser microdissection, confocal microscopy, mass spectrometry, liquid chromatography) and also technologies based on polymerase chain reaction and hybridization (biological microchips)*.

Today doctors can detect at an early stage genetic pathologies for the benefit of future parents who wish to avoid the risk of having children with acute hereditary disorders. Some families, in which such risks are especially high, resort to what medics call extracorporal fertilization. Detecting damaged genes even before the implantation of an embryo increases chances of giving birth to healthy progeny. And all one needs for this diagnosis is one single cell. Experts of the MMA Sechenov Research Institute of Molecular Medicine have completed another stage of related research and are now conducting practical trials. The same Institute is working on a system of DNA-markers which detect a patient's predisposition to breast cancer, lympholeucosis. By observing changes of DNA sections discovered during annual prophylactic medical examinations doctors can also identify other oncological, cardio-vascular, endocrinal and immunological pathologies.*

As for our country with its growing rates of what we call socially significant ailments, including infections, it is very important to work out scientific bases for issuing "genetic passports" and databases. And some of the elements of such future system (such as "personal maps of reproductive health") can be implemented even now. But does that mean that the traditional outpatient documents with clinical analyses data will soon be scrapped and replaced with "genomic" ones? Doubts on such innovations were expressed by Acad. N. Bochkov, Vice-President of the Russian medical Academy. In his opinion studies of body organs and tissues at the molecular level, important as they are, is only an addition to the traditional medical checks or examinations.

And now one more area of molecular diagnostics-studies of effectiveness of medicinal preparations. We know that one and the same preparation can cause very different responses in different patients, depending on their genotypes. Bearing this in mind, one can avoid negative side-effects, choosing the most effective cures and their doses. In the opinion of Acad. Paltsev it is now possible to translate into practice the old principle of Russian medicine, proclaimed some two centuries ago at the Medical Department of the Moscow University - "we cure not an ailment, but an ailing patient." And thanks to the accumulation of data on what they call the "individual genomic status" it has been possible to start research in new fields of medicine-genetic epidemiology and pharmacogenetics. Medicinal preparations intended for absolutely exact targets and free from any undesirable side-effects-as different from the currently available medicines-is the promising "tomorrow of pharmacology" which is not too far away.

GENETIC ENGINEERING

Decoding of the human genome has accelerated the development of new methods of molecular medicine. It is now possible to selectively influence the hereditary apparatus of the cell-suppress "excessive" functions of genes - "switch them off" - which needs to be done against different kinds of malignancies (progress in this field has been discussed by Acad. G. Georgiev, Director of the RAS Institute of Biology of Gene, and Acad. L. Kiselev, Head of Department of the RAS Institute of Molecular Biology named after V. Engelgardt). It will also be possible to correct the functioning of defective sections of DNA-kind of repair them. Methods of genetic therapy are quite effective not only against cancer, but also atherosclerosis, nervous and psychic disorders.

One of the most complicated problems, which is still unresolved, consists in producing in lab conditions medicinal structures of micro-and even nanodimentions which can "activate" or "deactivate" certain genes and deliver them to certain sections of a pathologically affected cell. Today scientists are working on what they call safe vector systems, kind of "pilots" which can easily find their way in the ocean of different body cells in order to deliver the necessary structures to the predetermined "targets".

From the start of the 1990s, when the first experiments in genetic therapy were conducted, large factual material has been accumulated in the world (during one and a half decades a total of 50 thous. patients have been treated in this way). And the results have not been all the same. Acad. Bochkov pointed out that some of the expectations were in vain. He gave as an example attempts of treatment of patients with a very grave illness-critical ischemia of legs. Doctors fail in their attempts to restore normal blood circulation by pharmacopeial methods for long periods of time and they have to resort to the amputation of the necrotic organs - the patient becomes an invalid. A solution to the problem has been on the agenda of experts of the RAS Institute of Molecular Genetics and the Russian Research Center of Surgery of our Medical Academy. They developed an original genetic-engineering structure with a gene of angiogenine which, when introduced into the affected tissues, can activate the processes of neoan-giogenesis (restoration of a new network of vessels). That means that doctors now can save patients who were traditionally regarded as hopeless.

IS TRUNK CELL UNIVERSAL?

The results of the conference on trunk cells held at the AKADEM-GORODOK Center in Novosibirsk (October 2004) were discussed by Acad. V. Vlasov, Director of the Institute of Chemical Biology and Fundamental Medicine of the RAS Siberian Branch. On problems of genetic therapy he said: "It is easy to introduce a gene into a cell when the latter is in a test-tube and can be influenced by physical methods. But when dealing with patients, such methods are unacceptable: the compounds produced cannot "force their way" to their "destination". And a gene can get into a chromosome not where it was intended, but in some place else and cause lots of problems. But the problem is solved when trunk cells

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come into play. They can be put into a test-tube, treated with a genetic structure, cleared of the "wastes" and then multiply them without any restrictions and then finally administer them to the patient. The associated prospects are really dazzling!"*

The problems of fundamental medical-biological studies were also on the agenda of the Moscow Conference. Since 1998, when experts demonstrated for the first time the possibility of their separation and cultivation, they have been in the focus of attention of not only scientists, but clinicists who were eagerly waiting for new remedies of this kind**. Today there are more than 200 banks of trunk cells (stores of umbilical cord blood of newborn). For the treatment of babies sick with leucosis they are intertied into a common network. Unfortunately in Russia there is no necessary legal base for medical establishments of this kind. This is taken advantage of by shady commercial structures which offer their questionable serviced for "rejuvenation" of patients or for the treatment of cancer-claims that discredit the genuine scientific achievements.

For example, it has been proved that in cases of acute myocardial infarction and ischemia the restoration of tissues occurs through the supply into the affected area of trunk cells of bone marrow. By increasing their concentration in the affected area by special methods it is possible to accelerate the process of regeneration (preliminary results obtained in the clinic of the St. Petersburg State Medical University named after I. Pavlov, give grounds for cautious optimism).

Needless to say that the main function of these remarkable cells is creativity. As a result of reprocessing of the genome (a very complicated mechanism of this phenomenon is still waiting for explanation) they can turn into any body cells. During the intrauterine period they participate in the formation of organs and tissues, and after birth and subsequent life-in their "construction" and "repairs". But in pathological processes (such as atherosclerosis) the same cells, as has been found out, accentuate them due to certain causes. In the opinion of Acad. V. Smirnov (Scientific Research Institute of Experimental Cardiology of the Russian Medical Academy), vessels stenosis them occurs not without the participation of stromal trunk cells of the bone marrow, circulating in peripheral blood. By eliminating defects in the vessel walls, caused by inflammation, they become "building material" for atherosclerotic patches.

Speaking of the advantages of trunk cells in supporting the vital body functions, participants of the Moscow conference noted their potential role, in the treatment of many ailments, including oncological ones. In order to avoid the problem of compatibility it is desirable to use cells of the patient himself (autological ones). After their separation they can be multiplied (in the opinion of some specialists this process, which looks hypothetically endless, does have its limitations: at some stage of new and new divisions there are possibilities of mutations), and then, after pre-differentiation, if necessary, these cells can be reintroduced into the patient's organism.

Can trunk cells be regarded as universal? This question was on the agenda of a "round table" conducted within the framework of the conference. The participants agreed that a simple answer to that question is hardly possible-the available store of knowledge about biological mechanisms, to say nothing about their management, is very small. Some interesting results, however, were reported by researchers of the RAS Institute of Biology of Development named after N. Koltsov. They have developed unique methods of skin healing from burns and trophic ulcers with the help of epithelial truck cells. This demonstrates the really promising nature of such technologies***.

MICROBIAL MENACE

As we know from history, scientific discoveries have not always been a blessing for mankind. In the 20th century this "conflict" involved, above all, nuclear physics, and in our day and age attention is focused on molecular biology. Acad. A. Spirin (RAS) pointed out that achievements in this particular field can be used for developing lethal weapons of a new generation****. The possibility of conducting secret studies and tests (many "civilian" and "defense" technologies are identical), low costs of production (it is enough to have a small laboratory with a limited staff), unusually difficult diagnostics (it is very hard to tell pathogenic DNA and RNA from the ordinary ones), accessibility of information (can be picked up from Internet) - these factors alone make bioterrorism one of the potential threats and the problem of biosafety - vitally important for the international community.

In the campaign against infectious diseases, whose rates, unfortunately, keep growing, great hopes have been pinned over the past 50 years on universal vaccination. But such plans remain unfulfilled because of the appearance of many new infections (HIV, "chicken flu", etc.), to say nothing of the threat of a "revival" of some common ailments considered eliminated. That means that the world of microorganisms has not been fully investigated yet. According to RAS Corresponding Member S. Netesov (VEKTOR Research Center, Novosibirsk region).***** Only some 15 percent of microbes on this planet have been discovered and identified, and as for viruses of man, only one fifth of their expected number have been investigated. Incidentally, it was in 1977 that the last case of smallpox infection was registered in the world and the World Health Organization decided that the disease was eliminated. But the cancellation of obligatory vaccinations has created a situation in which more than half of Russia's population are

now exposed to that dangerous disease. Apprehensions about consequences of this kind were expressed at the conference by Acad. G. Onishchenko, Chief Sanitary Doctor of the Russian Federation. And his apprehensions have been backed by recent local outbreaks in several countries of smallpox of cows and monkeys which infected people.

So, what is the evolutionary link between the three aforesaid orthopoxyviruses? What about their common "forefather" which has become the greatest epidemic menace today? For dealing with these difficult questions researchers of the VEKTOR Federal Research Center have decoded their complete genomes (some of the studies were conducted in parallel in Russia and the United States) and their levels of organization were compared. And it was established that the role of the "forefather" most likely belongs to the pathogen of cow smallpox. Experts warned that as a result of possible mutations it can also affect man-a conclusion which puts micro-biologists on guard in their studies of the dynamics of the process.

Among the agents, or carriers of infections identified over the last quarter of a century a leading role belongs to viruses although bacteria are also not ruled out. Among them is the causal agent of legionnaires' disease - legionella. The bacteria dwells in lakes and ponds on amoeba and infusoria and presents no immediate threat to people. But the situation is changed with the advent of technogenic factors. In systems of water supply and air conditioning at temperatures of 25 - 45°C bacteria rapidly multiply, producing biosediments on the walls of tubes and pipes. At high concentrations of the bacteria in finely dispersed aerosols (such as in industrial workshops, restaurants, cruise liners etc.) they are inhaled by people, causing acute pneumonia with death rates of 10 - 15 percent.

This happens because the disease is not identified at early stages and patients are usually treated against pneumococcal infections.

In the opinion of Prof. I. Tartakovsky, Dr. Sc. (Biol.) of the Institute of Epidemiology and Microbiology named after N. Gamalei of the Russian Medical Academy, for preventing acute complications it is necessary to have not only special vaccines, but to maintain constant monitoring of potentially dangerous objects generating aerosols. That means that the aforesaid example proves on the one hand that in certain "man-made" conditions some harmless microbe can turn "aggressor". On the other hand, it stresses the importance of having all necessary scientific instruments for the timely detection of dangerous pathogens. Our safety can not be guaranteed without an accelerated development of fundamental biological, and of the associated molecular, medical studies.

The International Medical Forum in Moscow adopted a message to the President and the Government of the Russian Federation stressing the importance of development and adoption of a Federal Program "Molecular Medicine and Biosafety" for a period of not later than 2005 - 2009. It says that we risk to find ourselves in a situation when the rate of growth of the numbers of socially important ailments will exceed the critical level and we shall be unable to counter this threat. We in Russia have a chance to develop one of the most promising branches of modern medical science without making the country dependent on foreign research. "We have a sufficient research potential of our own to make this branch competitive on the world market. But we can utilize this potential only with an adequate and timely support of the state."